Generation and conjugate additions of o-quinone methides under mild base conditions: Rapid synthesis of n-substituted aryl glycine derivatives

Article abstract of DOI:10.1002/ejoc.201301018

A one-step approach was observed to give N-substituted aryl glycine derivatives in good to excellent yields (up to 93 %) from (ortho-hydroxymethyl) aryl benzoates. A cascade mechanism was proposed for the generation and in situ conjugate addition of the ortho-quinone methides. This mechanism is strongly supported by our subsequent findings that tertiary amines could promote the process. Different functional groups on the (ortho-hydroxymethyl)aryl benzoates and various amines were investigated to explore the scope of this cascade process. The substituents on the substrates strongly affected the reaction time and yield, and various primary and secondary amines were used as nucleophiles. The addition of tertiary amines enhanced the addition process for less basic nucleophiles. A one-step cascade approach was observed to give N-substituted aryl glycine derivatives from (ortho-hydroxymethyl)aryl benzoates under very mild conditions. The proposed mechanism involves the generation of an ortho-quinone methide and its in situ conjugate addition. Various substituent groups on the substrate and different amines as the nucleophile were investigated. Copyright

Full text of DOI:10.1002/ejoc.201301018

FULL PAPER
DOI: 10.1002/ejoc.201301018
Generation and Conjugate Additions of o-Quinone Methides Under Mild Base
Conditions: Rapid Synthesis of N-Substituted Aryl Glycine Derivatives
Wei Wang,[a] Zhong Zheng,[a] Xiangmin Wang,[a] and Jinchun Chen*[a]
Keywords: Domino reactions / Michael addition / Reactive intermediates / Amines / Amino acids
A one-step approach was observed to give N-substituted aryl
glycine derivatives in good to excellent yields (up to 93%)
tional groups on the (ortho-hydroxymethyl)aryl benzoates
and various amines were investigated to explore the scope
of this cascade process. The substituents on the substrates
strongly affected the reaction time and yield, and various pri-
from (ortho-hydroxymethyl)aryl benzoates.
A
cascade
mechanism was proposed for the generation and in situ con-
jugate addition of the ortho-quinone methides. This mecha- mary and secondary amines were used as nucleophiles. The
nism is strongly supported by our subsequent findings that
tertiary amines could promote the process. Different func-
addition of tertiary amines enhanced the addition process for
less basic nucleophiles.
further development of efficient and practical methods,
which minimize time, cost, employment of special reagents,
and steps, to generate o-quinone methide intermediates still
remains highly desirable.
Introduction
As a class of useful transient intermediates, o-quinone
methides are widely employed in the syntheses of various
organic compounds[1] and have been reported as crucial
cytotoxins that are responsible for the functioning of agents
such as antitumor drugs, antibiotics, and DNA alkylators
in biochemistry and medical chemistry.[2] o-Quinone meth-
ides can undergo several important reactions, including
conjugate additions as well as intermolecular and intramo-
lecular cycloadditions. On account of this high reactivity,
the field of research to develop methods to generate o-quin-
one methides has been extensive for decades.[3] In the past
decade, methods to generate o-quinone methides relied
mainly on thermal initiation,[4a–4c] oxidation processes,[4d]
photochemical facilitation,[4e–4h] a retro-Diels–Alder reac-
tion,[4i] and either strong acids[4j–4l] or powerful bases.[4m,4n]
Despite their extensive applications, these methods still have
some limitations, which include the multiple steps needed
to build the o-quinone methide precursors, harsh reaction
conditions, and low yields. As a consequence, the demand
for alternate efficient methods has encouraged the extra de-
velopment of new ways to generate o-quinone methides. Re-
cently, several other approaches were reported that include
a fluoride-induced desilylation,[5a,5b] the utilization of tran-
sition-metal complexes,[5c] a Knoevenagel-type condensa-
tion,[5d] and a base-mediated desulfonylation.[5e] Consider-
ing their importance as active intermediates and their short
lifetime as a result of their potential for dimerization, the
Non-proteinogenic aryl glycines and their derivatives are
a class of attractive substances that are used as building
blocks in natural product syntheses and as biologically
active compounds in drug research.[6] Among different
aromatic units, aryl glycine acids are used to efficiently pro-
duce benzoxazines,[7] tetrahydroisoquinolines,[8] and several
other natural products.[9] Moreover, enantiopure aryl gly-
cine derivatives could serve as chiral ligands in the prepara-
tion of transition-metal complexes.[6a,10] As the classical
Mannich procedure is only suitable to synthesize a few aryl
glycines that are derived from highly electron-rich arom-
atics,[11] alternate approaches to prepare these compounds
have been developed. In general, the synthetic routes, which
start from 2-imidoylphenols,[10] O’Donnell’s Schiff bases,[12]
an N,O-acetal,[13] or arylglyoxylates[14] often require
multistep procedures, and the approaches from arylzinc rea-
gents[15] and glycine cation equivalents[16] are limited to sec-
ondary amines. Herein, we report an undiscovered o-quin-
one methide generation process that starts from (ortho-
hydroxymethyl)aryl benzoates and takes place under very
mild conditions to allow for the efficient syntheses of vari-
ous N-substituted (ortho-hydroxy)aryl glycine esters.
Results and Discussion
[a] School of Chemistry and Chemical Engineering, Yantai
University,
During the deprotection process to remove the benzoyl
group of (ortho-hydroxymethyl)aryl benzoate 1, we found
that the substance decomposed under various classical inor-
ganic base conditions. However, when n-propylamine was
used as the base in toluene,[17] a phenolic product did not
Yanstai 246005, P. R. China
E-mail: jinchunchengroup@163.com
http://www.chem.ytu.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301018.
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W. Wang, Z. Zheng, X. Wang, J. Chen
FULL PAPER
form, but instead, the much less polar product 2 (compare motes the rearrangement and the nucleophile of the conju-
to 1 by TLC analysis) was obtained in high yield. It was gate addition (see Scheme 2). This rearrangement process
difficult to determine the exact structure of 2 by spectro- with the benzoyl group is somewhat similar to the genera-
scopic analysis, but we treated it with di-tert-butyl di- tion strategy by the Pettus group, which used tert-butyl-
carbonate to give compound 5 in 95% yield, and we eventu- carbonyl-protected phenones that were initiated by using an
ally identified 2 as the N-propyl aryl glycine ester. It is organometallic reagent under low temperature.[18] However,
worth noting that benzoyl n-propylamide was not de- the rearrangement with the benzoyl group requires much
tected,[17] but a benzoic acid amine salt was observed during milder conditions than those for the tert-butylcarbonyl
the reaction process. When we treated (ortho-hydroxy)- group, which allows for the generation and consumption
benzyl alcohol 4 with n-propylamine under the same condi- of the ortho-quinone methides under ambient conditions.
tions, N-propyl aryl glycine ester 2 was also obtained al- Furthermore, compound 2 is less polar than (ortho-
though in a much lower yield (45%). Furthermore, when hydroxymethyl)aryl benzoate 1, as the typical absorption
compounds 6 and 7 were treated under the same conditions, peaks from the OH and NH groups do not exist in its IR
the corresponding phenolic products were afforded in high spectrum. Therefore, we surmised that two strong intramo-
yields (see Scheme 1). These results indicate that compound lecular hydrogen bonds exist in this structure to contribute
1 underwent a new reaction in the presence of n-propyl- to the reduced polarity, (see Scheme 3).
amine, instead of a simple deprotection, and that the ben-
zoyl group and ortho-positioned carbinol substituent were
vital factors of this cascade process. Because the acetyl
group of compound 6 is directly cleaved with n-propyl-
amine, we believe that the benzoyl group is more stable than
the acetyl group under these conditions, and it is, therefore,
more difficult for the benzoyl group to undergo an amino-
lysis by treatment with an amine.
Scheme 2. Suggested reaction mechanism in which n-propylamine
serves both as base and nucleophile.
Scheme 3. Two intramolecular hydrogen bonds of compound 2 lead
to its reduced polarity. This is supported by IR analysis. The typical
OH (3500–3200 cm–1) and NH (3500–3300 cm–1) absorption peaks
are not present in spectrum (see Supporting Information).
To test the scope of this cascade process, we developed a
new protocol for the syntheses of N-substituted aryl glycine
esters. Starting from various substituted phenols and the
Scheme 1. Initial screening of suitable substrates for the cascade
process (Boc = tert-butoxycarbonyl).
combination of phenols with glyoxylate by using a Friedel–
On the basis of the structure of compound 2, we propose Crafts reaction,[19] we carried out the selective protection of
that an o-quinone methide was generated as an intermediate phenolic hydroxy group[20] and the n-propylamine-mediated
during an intramolecular rearrangement of 1 and that this cascade process. The results are shown in Table 1. It can
intermediate was subsequently trapped in situ by n-propyl- be seen that the reactivity of the (ortho-hydroxymethyl)aryl
amine to produce the product.[3] In this transformation, n- benzoates is strongly affected by the substituent groups on
propylamine has two roles, that is, the reagent that pro- the aromatic ring. Substrates 1a, 1b, and 1c, which contain
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Generation and Conjugate Additions of o-Quinone Methides
Table 1. Survey of substituents on the aromatic ring.
Substrate
R1
R2
R3
R4
Product
Time [h]
% Yield[a]
1a
1aЈ
1b
1bЈ
1c
1cЈ
1d
1dЈ
1e
1eЈ
1f
1fЈ
1g
Me
Me
H
H
H
OCH2O
OCH2O
Bz
H
Bz
H
Bz
H
Bz
H
Bz
H
Bz
H
Bz
H
Bz
H
2a
0.5
3
0.5
3
2
3
5
3
8
3
15
3
24
3
36
3
93
49
92
45
89
33
63 (24)
15
56 (30)
12
30 (53)
8
2a
OMe
OMe
OMe
OMe
Me
Me
Me
Me
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
Me
Me
H
H
Cl
Cl
2b
2b
2c
H
2c
OMe
OMe
H
H
H
H
H
H
H
2d + 3d
2d
2e + 3e
2e
2f + 3f
2f
2g + 3g
2g
2h + 3h
–
23 (59)
5
12 (67)
–
1gЈ
1h
1hЈ
H
H
[a] Isolated yield.
a strong electron-donating group para to the carbinol, re- the concentration of the nucleophile at a relatively low level,
quired a shorter reaction time, and the aminolysis of ethyl and slow down the amidation process. With the addition of
ester was not observed. Substates 1d and 1e, which contain up to 2 equiv. of triethylamine and 2 equiv. of n-propyl-
a weak electron-donating group para to the carbinol, re- amine in the reaction system, the reaction times of 1d–1f
quired a longer reaction time and afforded a small amount were reduced to less than 3 h, and further amidation was
of the amidation product. For substrates such as 1f–1h that effectively controlled (see Table 2). This fact supported the
do not contain an electron-donating group para to the car- anionic o-quinone methide generation mechanism that we
binol or have an electron-withdrawing group on the aro- previously proposed and suggested that those electron-de-
matic ring, a much longer reaction time was needed. In ficient aryl benzoate derivatives needed more basic condi-
these cases, most of the products underwent further amid- tions to generate the o-quinone methides quickly.
ation, but the total yields of both products remained high.
As shown in Table 1, the yields of the reactions that
We subsequently discovered that the amidation of elec- started from the (ortho-hydroxymethyl)aryl phenols are
tron-deficient substances could be efficiently avoided by the lower than the corresponding benzoates under the same re-
addition of tertiary amines such as triethylamine or diiso- action conditions. As the substituents on the aromatic ring
propylethylamine. The basicity of reaction system would in- of the phenols are the same as those of the corresponding
crease by this addition, and as a result, this which would aryl benzoates, we believe that the acidity of phenolic
stimulate the generation of the ortho-quinone methide, keep hydroxy group decreased the basicity of the system and,
Table 2. Investigation of addition of tertiary amine to suppress amidation.
Substrate
R1
R2
R3
TEA [equiv.][a]
Product
Time [h]
% Yield[b]
1d
1e
1f
1g
1h
OMe
H
H
H
H
Me
Me
H
H
H
H
H
Me
H
Cl
1
1.5
2
2
2
2d
1.5
1.5
2
3
4
86
2e + 3e
2f + 3f
2g + 3g
2h + 3h
81 (3)
78 (5)
74 (10)
71 (12)
[a] TEA = triethylamine. [b] Isolated yield.
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W. Wang, Z. Zheng, X. Wang, J. Chen
FULL PAPER
thereby, hindered the generation of the o-quinone methide.
This hypothesis is supported by the results in Table 1, in
which the yields of the reactions of various aryl phenols
decreased with the increasing acidity of phenolic hydroxy
group. No reaction occurred when there was an electron-
withdrawing group para to the phenolic hydroxy group
(e.g., 1hЈ). This could be a consequence of the increased
acidity of the phenolic hydroxy group, which formed a salt
directly with the amine instead of underwent a rearrange-
ment reaction. It is worth noting that the self-polymeriza-
tion of o-quinone methides was not observed in all cases.
This could be a result of the ester moiety in the substance,
which reduced the electron density of the o-quinone me-
thides and, therefore, lowered the rate of self-polymeriza-
tion.
To explore the scope of the amines in this reaction,
(ortho-hydroxymethyl)aryl benzoate 1 was treated with dif-
ferent primary and secondary amines (see Table 3). When
primary amines were used, the reaction times depended on
their basicity. Strongly basic amines underwent the cascade
process directly to give the corresponding N-substituted
aryl glycine esters 8, 9, and 11. Those nucleophiles that were
less basic needed a longer reaction time and a slighter
Conclusions
In summary, we have described a new mild protocol,
which is mediated by amines, for the generation of o-quin-
one methides from (ortho-hydroxymethyl)aryl benzoates.
This method was applied it to the syntheses of various N-
substituted (ortho-hydroxy)aryl glycine esters. The proposed
reaction mechanism for this process involves a base-medi-
ated rearrangement of the benzoyl group to afford an o-
quinone methide, which can undergo an in situ 1,4-conju-
gate addition with primary and secondary amines. The mild
reaction conditions, simple workup, and wide substrate
scope combine to make this a useful addition to ortho-quin-
one methide chemistry. Detailed mechanistic studies of this
process and its utilization in organic synthesis are in pro-
gress in our laboratory.
Experimental Section
General Procedure to the Syntheses of N-Substituted Aryl Glycine
Derivatives: To a stirred solution of the (ortho-hydroxymethyl)aryl
benzoate (1.0 mmol) in toluene (5 mL) was added the primary or
secondary amine (3.5 mmol). The reaction mixture was stirred at
higher temperature, or they were not sufficiently basic to room temperature, and TLC was used to monitor the reaction.
When TLC showed complete consumption of substrates, the reac-
tion mixture was diluted with ethyl acetate (50 mL). The resulting
solution was washed with water (2ϫ 50 mL) and brine (50 mL)
and then dried with sodium sulfate. After filtration and evaporation
of the solvent under reduced pressure, the crude product was puri-
fied by flash chromatography on silica gel (petroleum ether/ethyl
acetate, gradient 20:1 to 4:1 v/v) to afford the N-substituted aryl
glycine derivative.
generate the o-quinone methide. This was the case with 2-
chloroaniline and 3-[(tert-butyldimethylsilyl)oxy]aniline,
and in such a circumstance, an additional amount of a terti-
ary amine promoted the generation of the o-quinone
methide to afford the corresponding N-substituted aryl gly-
cine esters in high yields. Secondary amines required a
shorter reaction time on account of their increased basicity.
When (R)-1-phenylethan-1-amine was used as nucleophile,
two epimers were obtained in a ratio of over 2:1, indicating
a possible utilization for the syntheses of enantiopure aryl
glycine derivatives.
Improved General Procedure to the Syntheses of N-Substituted Aryl
Glycine Derivatives: To
a stirred solution of the (ortho-hy-
droxymethyl)aryl benzoate (1.0 mmol) in toluene (5 mL) were
added the primary or secondary amine (2.0 mmol) and triethyl-
amine (2.0 mmol). The reaction mixture was stirred at room tem-
perature, and TLC was used to monitor the reaction. When the
substrates were completely consumed, the reaction was diluted with
ethyl acetate (50 mL). The resulting solution was washed with
water (2ϫ 50 mL) and brine (50 mL) and then dried with sodium
sulfate. After filtration and evaporation of the solvent under re-
duced pressure, the crude product was purified by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate, gradient 20:1 to
4:1 v/v) to afford the N-substituted aryl glycine derivative.
Table 3. Survey of amines as nucleophile.
Ethyl 2-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-(propylamino)acetate
1
(2): H NMR (400 MHz, CDCl3, 293 K): δ = 6.55 (s, 1 H, PhH),
6.38 (s, 1 H, PhH), 5.87 (s, 2 H, OCH2O), 4.32 (s, 1 H, α-H), 4.27–
R1
R2 Product Temp Time [h] % Yield
3
4.11 (m, 2 H, OCH2CH3), 2.60 (t, JH,H = 6.8 Hz,
2 H,
3
NCH2CH2CH3), 1.58 (hex, JH,H = 7.2 Hz, 2 H, NCH2CH2CH3),
CH2=CHCH2
PhCH2
Ph
(R)-PhCHCH3
m-tBuMe2SiOPh
o-ClPh
–CH2CH2OCH2CH2–
–CH2CH2CH2CH2–
H
H
H
H
H
H
8
9
r.t.
r.t.
40 °C
r.t.
r.t.
r.t.
2
2.5
2
2
2
92
91
88
3
3
1.23 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3), 0.94 (t, JH,H = 7.3 Hz,
3 H, NCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.08, 153.15, 148.23, 140.24, 110.87, 108.80, 100.92, 99.17, 64.76,
10
11[a]
12
13
14
15
16
90[b]
88[c]
91[c]
89
61.82, 48.94, 22.55, 14.06, 11.54, 8.48 ppm. IR (film): ν = 3055,
˜
2
2966, 2917, 1733, 1632, 1503, 1479, 1385, 1265, 1191, 1039, 938,
896, 853, 738, 704 cm–1. HRMS (ESI+): calcd. for C14H20NO5 [M
+ H]+ 282.1341; found 282.1346.
r.t.
0.5
0.5
0.5
r.t.
r.t.
91
86
Et
Et
Ethyl
2-(6-Hydroxy-7-methylbenzo[d][1,3]dioxol-5-yl)-2-(propyl-
[a] A pair of epimers with a diastereomeric ratio of 2:1. [b] Total
yield of two epimers. [c] With additional 1 equiv. of triethylamine.
This reaction did not occur without this additional tertiary amine.
1
amino)acetate (2a): H NMR (400 MHz, CDCl3, 293 K): δ = 6.39
(s, 1 H, PhH), 5.87 (d, 2JH,H = 1.6 Hz, 2 H, OCH2O), 4.30 (s, 1 H,
8302
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Generation and Conjugate Additions of o-Quinone Methides
3
α-H), 4.28–4.11 (m, 2 H, OCH2CH3), 2.59 (t, JH,H = 6.8 Hz, 2 H,
Ethyl 2-(2-Hydroxy-5-methylphenyl)-2-(propylamino)acetate (2f):
NCH2CH2CH3), 2.09 (s, 3 H, PhMe), 1.57 (hex, JH,H = 7.2 Hz, 2 1H NMR (400 MHz, CDCl3, 293 K): δ = 6.98 (d, JH,H = 8.2 Hz,
3
3
3
3
H, NCH2CH2CH3), 1.23 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3), 0.93
1 H, PhH), 6.85 (s, 1 H, PhH), 6.72 (d, JH,H = 8.2 Hz, 1 H, PhH),
3
(t, JH,H
=
7.3 Hz,
3
H, NCH2CH2CH3) ppm. 13C NMR
4.41 (s, 1 H, α-H), 4.28–4.16 (m, 2 H, OCH2CH3), 2.65–2.54 (m, 2
(100 MHz, CDCl3): δ = 171.21, 151.40, 146.50, 139.19, 110.34,
108.53, 105.86, 100.54, 64.84, 61.60, 48.82, 22.51, 13.98, 11.47, 2 H, NCH2CH2CH3), 1.23 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3),
H, NCH2CH2CH3), 2.25 (s, 3 H, PhMe), 1.57 (hex, 3JH,H = 7.2 Hz,
3
3
8.48 ppm. IR (film): ν = 2965, 2933, 2876, 1737, 1645, 1586, 1500,
0.93 (t, JH,H = 7.2 Hz, 3 H, NCH2CH2CH3) ppm. 13C NMR
˜
1470, 1423, 1380, 1259, 1201, 1094, 1026, 938, 848, 735, 702 cm–1. (100 MHz, CDCl3): δ = 171.23, 155.30, 130.0, 129.94, 128.13,
HRMS (ESI+): calcd. for C15H22NO5 [M + H]+ 296.1498; found
296.1502.
119.70, 116.78, 65.08, 61.72, 49.07, 22.64, 20.46, 14.05, 11.53 ppm.
IR (film): ν = 3319, 2961, 2926, 2873, 1735, 1598, 1500, 1460, 1369,
˜
1261, 1231, 1159, 1117, 1026, 957, 858, 819, 772, 542 cm–1. HRMS
(ESI+): calcd. for C14H22NO3 [M + H]+ 252.1600; found 252.1598.
Ethyl 2-(2-Hydroxy-4,5-dimethoxyphenyl)-2-(propylamino)acetate
(2b): H NMR (400 MHz, CDCl3, 293 K): δ = 6.59 (s, 1 H, PhH),
1
Ethyl 2-(2-Hydroxyphenyl)-2-(propylamino)acetate (2g): 1H NMR
6.42 (s, 1 H, PhH), 4.37 (s, 1 H, α-H), 4.27–4.11 (m, 2 H,
OCH2CH3), 3.83 (s, 3 H, PhOMe), 3.82 (s, 3 H, PhOMe), 2.63 (t,
3
(400 MHz, CDCl3, 293 K): δ = 7.18 (m, 1 H, PhH), 7.05 (d, JH,H
3JH,H = 6.8 Hz, 2 H, NCH2CH2CH3), 1.58 (hex, JH,H = 7.2 Hz, 2
3
= 7.2 Hz, 1 H, PhH), 6.81 (m, 2 H, PhH), 4.46 (s, 1 H, α-H), 4.27–
4.09 (m, 2 H, OCH2CH3), 2.66–2.55 (m, 2 H, NCH2CH2CH3), 1.58
(hex, 3JH,H = 7.1 Hz, 2 H, NCH2CH2CH3), 1.22 (t, 3JH,H = 7.2 Hz,
3
H, NCH2CH2CH3), 1.23 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3), 0.95
3
(t, JH,H
= 7.3 Hz, 3
H, NCH2CH2CH3) ppm. 13C NMR
3
H, OCH2CH3), 0.93 (t, 3JH,H
=
7.3 Hz,
3
H,
(100 MHz, CDCl3): δ = 171.18, 152.19, 149.99, 141.70, 113.33,
109.97, 101.29, 64.70, 61.59, 56.65, 55.63, 49.03, 22.58, 13.96,
NCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.18,
157.79, 129.55, 129.47, 120.02, 119.08, 117.07, 65.09, 61.79, 49.11,
11.47 ppm. IR (film): ν = 2961, 2935, 2874, 1735, 1620, 1511, 1463,
˜
1383, 1301, 1210, 1120, 1027, 855 cm–1. HRMS (ESI+): calcd. for
C15H24NO5 [M + H]+ 298.1654; found 298.1655.
22.66, 14.04, 11.55 ppm. IR (film): ν = 3054, 2964, 2933, 2849,
˜
1732, 1590, 1491, 1470, 1408, 1265, 1229, 1155, 1103, 1026, 896,
854, 739, 704 cm–1. HRMS (ESI+): calcd. for C13H20NO3 [M +
H]+ 238.1443; found 238.1444.
Ethyl 2-(2-Hydroxy-4-methoxyphenyl)-2-(propylamino)acetate (2c):
1H NMR (400 MHz, CDCl3, 293 K): δ = 6.94 (d, JH,H = 8.0 Hz,
3
Ethyl 2-(5-Chloro-2-hydroxyphenyl)-2-(propylamino)acetate (2h): 1H
1 H, PhH), 6.35 (d, 3JH,H = 8.0 Hz, 1 H, PhH), 6.34 (s, 1 H, PhH),
3
NMR (400 MHz, CDCl3, 293 K): δ = 7.13 (dd, JH,H = 8.8 Hz,
4.41 (s, 1 H, α-H), 4.24–4.10 (m, 2 H, OCH2CH3), 3.73 (s, 3 H,
PhOMe), 2.64–2.54 (m, 2 H, NCH2CH2CH3), 1.56 (hex, JH,H
7.2 Hz, 2 H, NCH2CH2CH3), 1.20 (t, JH,H = 7.2 Hz, 3 H,
4
4JH,H = 2.1 Hz, 1 H, PhH), 7.05 (d, JH,H = 2.1 Hz, 1 H, PhH),
3
=
3
6.74 (d, JH,H = 8.8 Hz, 1 H, PhH), 4.39 (s, 1 H, α-H), 4.28–4.13
3
(m, 2 H, OCH2CH3), 2.65–2.53 (m, 2 H, NCH2CH2CH3), 1.57
3
OCH2CH3), 0.93 (t, JH,H = 7.3 Hz, 3 H, NCH2CH2CH3) ppm.
(hex, 3JH,H = 7.2 Hz, 2 H, NCH2CH2CH3), 1.23 (t, 3JH,H = 7.2 Hz,
13C NMR (100 MHz, CDCl3): δ = 171.13, 160.57, 158.80, 129.97,
3
H, OCH2CH3), 0.94 (t, 3JH,H
=
7.4 Hz,
3
H,
112.06, 105.10, 101.83, 64.29, 61.36, 54.82, 48.72, 22.41, 13.78,
11.31 ppm. IR (film): ν = 3320, 2962, 2935, 2875, 2838, 1733, 1622,
1589, 1511, 1463, 1386, 1289, 1265, 1227, 1201, 1160, 1119, 1101,
1059, 1033, 962, 836, 795, 736, 703, 639, 584, 471 cm–1. HRMS
(ESI+): calcd. for C14H22NO4 [M + H]+ 268.1549; found 268.1552.
NCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.47,
˜
156.45, 129.34, 129.24, 123.50, 121.27, 118.30, 64.67, 62.01, 49.08,
22.53 13.97, 11.46 ppm. IR (film): ν = 3323, 3055, 2965, 2935, 2876,
˜
1735, 1585, 1483, 1387, 1369, 1265, 1227, 1203, 1113, 1024, 957,
881, 858, 826, 739, 704, 650, 539 cm–1. HRMS (ESI+): calcd. for
C13H18NO3ClNa [M + Na]+ 294.0873; found 294.0871.
Ethyl
2-(2-Hydroxy-3-methoxy-4-methylphenyl)-2-(propylamino)-
acetate (2d): 1H NMR (500 MHz, CDCl3, 293 K): δ = 6.69 (d,
2-(2-Hydroxy-3-methoxy-4-methylphenyl)-N-propyl-2-(propylamino)-
3JH,H = 8.4 Hz, 1 H, PhH), 6.60 (d, JH,H = 8.4 Hz, 1 H, PhH),
3
1
acetamide (3d): H NMR (400 MHz, CDCl3, 293 K): δ = 6.70 (d,
3
3JH,H = 8.0 Hz, 1 H, PhH), 6.66 (d, JH,H = 8.0 Hz, 1 H, PhH),
4.45 (s, 1 H, α-H), 4.27–4.14 (m, 2 H, OCH2CH3), 3.83 (s, 3 H,
PhOMe), 2.65–2.55 (m, 2 H, NCH2CH2CH3), 2.24 (s, 3 H, PhMe),
5.81 (br. s, 1 H, CONH), 4.23 (s, 1 H, α-H), 3.83 (s, 3 H, PhOMe),
3.21–3.08 (m, 2 H, CONHCH2CH2CH3), 2.66–2.49 (m, 2 H,
NCH2CH2CH3), 2.27 (s, 3 H, PhMe), 1.63–1.50 (m, 2 H,
NCH2CH2CH3), 1.50–1.35 (m, 2 H, CONHCH2CH2CH3), 0.93 (t,
3
1.59–1.53 (m, 2 H, NCH2CH2CH3), 1.23 (t, JH,H = 5.6 Hz, 3 H,
3
OCH2CH3), 0.93 (t, JH,H = 6.0 Hz, 3 H, NCH2CH2CH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.21, 150.76, 146.48, 131.89,
3
3JH,H = 5.6 Hz, 3 H, NCH2CH2CH3), 0.81 (t, JH,H = 6.0 Hz, 3
123.89, 120.44, 118.84, 64.60, 61.70, 59.86, 49.04, 22.57, 15.86,
H, CONHCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
14.04, 11.53 ppm. IR (film): ν = 3054, 2965, 2932, 2854, 2305, 1732,
˜
1611, 1465, 1389, 1265, 1238, 1111, 1073, 1020, 896, 739, 704 cm–1.
HRMS (ESI+): calcd. for C15H24NO4 [M + H]+ 282.1705; found
282.1711.
170.61, 150.72, 146.78, 132.26, 123.60, 120.78, 119.47, 65.70, 59.65,
49.54, 41.21, 22.41, 22.38, 15.77, 11.41, 10.85 ppm. IR (KBr): ν =
˜
3418, 2963, 2933, 2875, 1655, 1532, 1463, 1394, 1269, 1240, 1153,
1111, 1073, 1020, 966, 932, 793, 771, 573 cm–1. HRMS (ESI+):
calcd. for C16H27N2O3 [M + H]+ 295.2022; found 295.2025.
Ethyl 2-(2-Hydroxy-4-methylphenyl)-2-(propylamino)acetate (2e):
1H NMR (400 MHz, CDCl3, 293 K): δ = 6.92 (d, JH,H = 7.6 Hz,
3
3
1 H, PhH), 6.64 (s, 1 H, PhH), 6.61 (d, JH,H = 7.6 Hz, 1 H, PhH),
2-(2-Hydroxy-4-methylphenyl)-N-propyl-2-(propylamino)acetamide
4.42 (s, 1 H, α-H), 4.27–4.11 (m, 2 H, OCH2CH3), 2.64–2.54 (m, (3e): 1H NMR (400 MHz, CDCl3, 293 K): δ = 6.92 (d, JH,H
=
3
2 H, NCH2CH2CH3), 2.27 (s, 3 H, PhMe), 1.61–1.56 (m, 2 H, 7.2 Hz, 1 H, PhH), 6.70 (s, 1 H, PhH), 6.73–6.63 (m, 2 H, PhH),
3
NCH2CH2CH3), 1.23 (t, JH,H = 7.2 Hz, 3 H, OCH2CH3), 0.93 (t, 5.70 (br. s, 1 H, CONH), 4.22 (s, 1 H, α-H), 3.20–3.10 (m, 2 H,
3JH,H = 7.2 Hz, 3 H, NCH2CH2CH3) ppm. 13C NMR (100 MHz, CONHCH2CH2CH3), 2.63–2.50 (m, 2 H, NCH2CH2CH3), 2.30 (s,
CDCl3): δ = 171.25, 157.49, 139.55, 129.28, 119.90, 117.56, 116.94, 3 H, PhMe), 1.61–1.50 (m, 2 H, NCH2CH2CH3), 1.46–1.35 (m, 2
3
64.74, 61.64, 48.98, 22.59, 21.12, 13.99, 11.48 ppm. IR (film): ν = H, CONHCH2CH2CH3), 0.92 (t, JH,H = 6.8 Hz, 3 H, NCH2CH2-
˜
3319, 2961, 2928, 2874, 1732, 1625, 1583, 1513, 1463, 1369, 1330,
1265, 1227, 1159, 1117, 1059, 1027, 955, 862, 799, 759, 735, 590,
552, 516, 467, 430 cm–1. HRMS (ESI+): calcd. for C14H22NO3 [M
+ H]+ 252.1600; found 252.1599.
CH3), 0.80 (t, 3JH,H = 7.0 Hz, 3 H, CONHCH2CH2CH3) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 170.78, 157.68, 140.15, 129.12,
120.29, 118.16, 117.41, 65.87, 49.62, 41.35, 22.51, 22.45, 21.16,
11.48, 10.95 ppm. IR (neat): ν = 3277, 3206, 2961, 2932, 2873,
˜
Eur. J. Org. Chem. 2013, 8299–8306
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8303

W. Wang, Z. Zheng, X. Wang, J. Chen
FULL PAPER
1644, 1611, 1573, 1511, 1474, 1456, 1383, 1266, 1223, 1150, 1114,
1073, 984, 965, 909, 882, 812, 757, 687, 586, 532, 486, 485 cm–1.
HRMS (ESI+): calcd. for C15H25N2O2 [M + H]+ 265.1916; found
265.1920.
1294, 1248, 1140, 1096, 1036, 1000, 935, 913, 858, 779, 743, 721,
519, 461, 443 cm–1. HRMS (ESI+): calcd. for C24H35NO9Na [M +
Na]+ 504.2210; found 504.2207.
Ethyl 2-(Allylamino)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)acetate
1
(8): H NMR (500 MHz, CDCl3, 293 K): δ = 6.52 (s, 1 H, PhH),
2-(2-Hydroxy-5-methylphenyl)-N-propyl-2-(propylamino)acetamide
3
(3f): 1H NMR (400 MHz, CDCl3, 293 K): δ = 7.05 (d, JH,H
=
6.40 (s, 1 H, PhH), 5.88 (s, 2 H, OCH2O), 5.90–5.81 (m, 1 H,
3
2
3
NCH2CH=CH2), 5.20 (dd, JH,H = 4.8 Hz, JH,H = 0.8 Hz, 1 H,
NCH2CH=CHH), 5.18 (br. s, 1 H, NCH2CH=CHH), 4.38 (s, 1 H,
8.0 Hz, 1 H, PhH), 6.86 (s, 1 H, PhH), 6.80 (d, JH,H = 8.0 Hz, 1
H, PhH), 5.70 (br. s, 1 H, CONH), 4.23 (s, 1 H, α-H), 3.21–3.08
( m , 2 H , C O N H C H 2 C H 2 C H 3 ) , 2 . 6 3 – 2 . 5 0 ( m , 2 H ,
NCH2CH2CH3), 2.28 (s, 3 H, PhMe), 1.57 (hex, JH,H = 7.3 Hz, 2
H , N C H 2 C H 2 C H 3 ) , 1 . 4 2 ( h e x , J H , H = 7 . 1 H z , 2 H ,
2
α-H), 4.26–4.13 (m, 2 H, OCH2CH3), 3.34 (ddt, JH,H = 11.2 Hz,
4
3
3JH,H = 4.6, JH,H = 1.0 Hz, 1 H), 3.20 (dd, 2JH,H = 11.2 Hz, JH,H
3
= 5.6 Hz, 1 H), 1.23 (t, JH,H = 5.6 Hz, 3 H, OCH2CH3) ppm. 13C
3
3
3
NMR (100 MHz, CDCl3): δ = 171.04, 153.06, 148.30, 140.34,
134.09, 118.01, 110.61, 108.99, 100.95, 99.21, 63.46, 61.86, 48.88,
C O N H C H 2 C H 2 C H 3 ) , 0 . 9 3 ( t , J H , H = 7 . 4 H z , 3 H ,
3
N C H 2 C H 2 C H 3 ) , 0 . 8 1 ( t , J H , H = 7 . 4 H z , 3 H ,
CONHCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
14.04 ppm. IR (film): ν = 3416, 3385, 2917, 2849, 1732, 1631, 1503,
˜
1478, 1443, 1384, 1301, 1189, 1156, 1111, 1067, 1037, 935 cm–1.
HRMS (ESI+): calcd. for C14H18NO5 [M + H]+ 280.1185; found
280.1192.
170.70, 155.45, 130.52, 129.71, 128.68, 120.26, 117.45, 66.12, 49.74,
41.41, 22.54, 22.51, 20.42, 11.52, 10.98 ppm. IR (KBr): ν = 3276,
˜
3105, 2958, 2930, 2873, 1640, 1617, 1578, 1471, 1454, 1424, 1383,
1347, 1322, 1286, 1254, 1225, 1154, 1130, 1113, 1049, 985, 963,
946, 900, 851, 819, 805, 730, 662, 602, 562, 535, 475 cm–1. HRMS
(ESI+): calcd. for C15H25N2O2 [M + H]+ 265.1916; found 265.1919.
Ethyl 2-(Benzylamino)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)acetate
1
(9): H NMR (400 MHz, CDCl3, 293 K): δ = 7.35–7.20 (m, 5 H,
2
benzylPhH), 6.52 (s, 1 H, PhH), 6.42 (s, 1 H, PhH), 5.82 (d, JH,H
1
= 1.8 Hz, 2 H, OCH2O), 4.31 (s, 1 H, α-H), 4.22–4.07 (m, 2 H,
2-(2-Hydroxyphenyl)-N-propyl-2-(propylamino)acetamide (3g): H
OCH2CH3), 3.84 (d, 2JH,H = 13.1 Hz, 2 H, benzylH), 3.65 (d, 2JH,H
NMR (400 MHz, CDCl3, 293 K): δ = 7.26–7.21 (m, 1 H, PhH),
3
3
=
13.2 Hz, 2 H, benzylH), 1.18 (t, JH,H
=
7.1 Hz, 3 H,
7.05 (d, JH,H = 7.2 Hz, 1 H, PhH), 6.88–6.84 (m, 2 H, PhH), 5.73
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.92,
3
(br. s, 1 H, CONH), 4.26 (s, 1 H, α-H), 3.15 (q, JH,H = 6.5 Hz, 2
H, CONHCH2CH2CH3), 2.63–2.50 (m, 2 H, NCH2CH2CH3), 1.56
153.00, 148.40, 140.43, 137.44, 128.77, 128.53, 127.78, 110.54,
3
3
109.14, 100.99, 99.26, 63.37, 61.88, 50.54, 14.03 ppm. IR (film): ν
˜
(hex, JH,H = 7.3 Hz, 2 H, NCH2CH2CH3), 1.40 (hex, JH,H
=
3
= 3319, 2916, 2849, 1731, 1631, 1501, 1478, 1409, 1384, 1299, 1185,
1151, 1111, 1066, 1038, 936, 856, 754, 700 cm–1. HRMS (ESI+):
calcd. for C17H17NO5Na [M + Na]+ 338.1004; found 338.1010.
7.2 Hz, 2 H, CONHCH2CH2CH3), 0.93 (t, JH,H = 7.4 Hz, 3 H,
3
N C H 2 C H 2 C H 3 ) , 0 . 8 0 ( t , J H , H = 7 . 4 H z , 3 H ,
CONHCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.57, 157.95, 129.97, 129.27, 120.55, 119.47, 117.64, 66.12, 49.69,
Ethyl 2-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-(phenylamino)acetate
(10): H NMR (400 MHz, CDCl3, 293 K): δ = 7.20–7.16 (m, 2 H,
1
41.40, 22.53, 22.45, 11.50, 10.95 ppm. IR (neat): ν = 3300, 3070,
˜
2963, 2933, 2875, 1653, 1589, 1533, 1490, 1458, 1411, 1383, 1259,
1152, 1102, 830, 754 cm–1. HRMS (ESI+): calcd. for C14H23N2O2
[M + H]+ 251.1760; found 251.1752.
NH2PhH), 6.83 (m, 1 H, NH2PhH), 6.73 (s, 1 H, PhH), 6.77–6.69
(m, 2 H, NH2PhH), 6.43 (s, 1 H, PhH), 5.88 (s, 2 H, OCH2O), 4.94
3
(s, 1 H, α-H), 4.33–4.09 (m, 2 H, OCH2CH3), 1.27 (t, JH,H
=
7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.44, 151.38, 148.39, 145.43, 141.36, 129.33, 129.33, 120.56,
115.48, 115.48, 112.89, 108.01, 101.19, 99.68, 62.47, 60.67,
2-(5-Chloro-2-hydroxyphenyl)-N-propyl-2-(propylamino)acetamide
3
(3h): 1H NMR (400 MHz, CDCl3, 293 K): δ = 7.18 (dd, JH,H
=
4
4
8.8 Hz, JH,H = 2.2 Hz, 1 H, PhH), 7.05 (d, JH,H = 2.1 Hz, 1 H,
PhH), 6.80 (d, 3JH,H = 8.8 Hz, 1 H, PhH), 5.88 (br. s, 1 H, CONH),
4.22 (s, 1 H, α-H), 3.24–3.10 (m, 2 H, CONHCH2CH2CH3), 2.62–
14.02 ppm. IR (KBr): ν = 3442, 3262, 2986, 2903, 1731, 1631, 1602,
˜
1500, 1488, 1442, 1433, 1306, 1232, 1195, 1168, 1154, 1117, 1103,
1069, 1043, 950, 932, 896, 871, 844, 820, 801, 752, 719, 692, 620,
613, 578, 547, 490 cm–1. HRMS (ESI+): calcd. for C17H17NO5Na
[M + Na]+ 338.1004; found 338.1010.
3
2.48 (m, 2 H, NCH2CH2CH3), 1.56 (hex, JH,H = 7.3 Hz, 2 H,
NCH2CH2CH3), 1.43 (hex, 3JH,H
CONHCH2CH2CH3), 0.93 (t, 3JH,H
=
=
=
7.2 Hz,
7.4 Hz,
7.4 Hz, 3
2
H,
H,
H,
3
NCH2CH2CH3),
0.83
(t,
3JH,H
Ethyl 2-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-{[(R)-1-phenylethyl]-
CONHCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
amino}acetate (11, mixture of epimers): 1H NMR (400 MHz,
3
169.97, 156.59, 129.85, 128.68, 124.03, 122.33, 119.09, 65.57, 49.73,
CDCl3, 293 K): δ = 7.39–7.24 (m, 7 H, PhH), 7.17 (d, JH,H
=
41.54, 22.53, 22.53, 11.51, 11.01 ppm. IR (KBr): ν = 3277, 3123,
˜
7.3 Hz, 1 H, PhH), 6.43 (s, 0.5 H, PhH), 6.36 (s, 2.5 H, PhH), 5.89
(d, JH,H = 5.4 Hz, 1 H, OCH2O), 5.84 (s, 2 H, OCH2O), 4.31
2
2960, 2933, 2875, 1668, 1639, 1599, 1577, 1499, 1477, 1451, 1421,
1382, 1361, 1344, 1315, 1274, 1249, 1220, 1170, 1146, 1112, 1071,
983, 962, 932, 908, 882, 815, 759, 726, 642, 605, 579, 528, 481 cm–1.
HRMS (ESI+): calcd. for C14H22N2O2Cl [M + H]+ 285.1370;
found 285.1369.
(s, 1 H, α-H), 4.37–4.16 (m, 2 H, OCH2CH3), 4.14–4.03 (m, 1 H,
3
OCH2CH3), 4.00 (s, 0.5 H, α-H), 3.82 (q, JH,H = 6.5 Hz, 1 H, α-
3
3
H), 3.73 (q, JH,H = 6.8 Hz, 0.5 H, α-H, PhH), 1.47 (t, JH,H
=
7.0 Hz, 4.5 H, PhCHMe), 1.27 (t, 3JH,H = 7.2 Hz, 3 H, OCH2CH3),
1.14 (t, 3JH,H = 7.2 Hz, 1.5 H, PhCHMe) ppm. IR (film): ν = 3054,
˜
Ethyl
2-[(tert-Butoxycarbonyl)(propyl)amino]-2-{6-[(tert-butoxy-
(5):
1H NMR
2985, 2926, 2305, 1730, 1633, 1503, 1480, 1265, 1235, 1156, 1114,
1039, 939, 896, 856, 739, 704, 546 cm–1. HRMS (ESI+): calcd. for
C19H22NO5 [M + H]+ 344.1498; found 344.1506.
carbonyl)oxy]benzo[d][1,3]dioxol-5-yl}acetate
(400 MHz, CDCl3, 293 K): δ = 6.80 (br. s, 1 H, PhH), 6.71 (br. s,
2
1 H, PhH), 5.99 (d, JH,H = 2.8 Hz, 2 H, OCH2O), 5.63 (br. s, 1
H), 5.57 (br. s, 1 H), 4.24–4.17 (m, 2 H, OCH2CH3), 3.16–2.92 (m,
Ethyl
2-({3-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)-2-(6-hyd-
2 H, NCH2CH2CH3), 1.53 (s, 9 H, tBuO), 1.47 (s, 9 H, tBuO), roxybenzo[d][1,3]dioxol-5-yl)acetate (12): 1H NMR (400 MHz,
3
3
1.30–1.20 (m, 5 H, OCH2CH3), 0.74 (t, JH,H = 7.3 Hz, 3 H,
CDCl3, 293 K): δ = 7.02 (s, JH,H = 8.0 Hz, 1 H, PhH), 6.72 (s, 1
NCH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.44, H, PhH), 6.42 (s, 1 H, PhH), 6.38–6.33 (m, 2 H, PhH), 6.22 (br. s,
2
147.85, 145.32, 144.04, 108.60, 107.87, 103.95, 101.91 83.71, 61.24,
58.27, 57.63, 47.65, 28.29, 27.53, 22.28, 21.79, 14.05, 11.24 ppm.
1 H, PhH), 5.90 (d, JH,H = 3. 9 Hz, 2 H, OCH2O), 4.91 (s, 1 H,
α-H), 4.32–4.19 (m, 2 H, OCH2CH3), 1.25 (t, 3JH,H = 7.0 Hz, 3 H,
OCH2CH3), 0.93 (s, 9 H, SiMe2tBu), 0.11 (s, 6 H, SiMe2tBu) ppm.
IR (neat): ν = 2977, 2931, 1760, 1694, 1634, 1506, 1485, 1394, 1368,
˜
8304
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8299–8306

Generation and Conjugate Additions of o-Quinone Methides
13C NMR (100 MHz, CDCl3): δ = 171.35, 156.61, 151.36, 148.40,
146.61, 141.41, 129.97, 112.83, 112.47, 108.92, 108.07, 107.39,
Acknowledgments
101.18, 99.72, 62.50, 60.81, 25.61, 14.02 ppm. IR (neat): ν = 3404,
˜
The authors thank the National Natural Science Foundation of
China (NSFC) for the financial support for this investigation (grant
number 20802062).
2956, 2930, 2896, 1731, 1602, 1504, 1483, 1441, 1409, 1390, 1370,
1295, 1259, 1196, 1121, 1039, 1003, 981, 938, 839, 782, 689, 665,
573, 493, 454 cm–1. HRMS (ESI+): calcd. for C23H31NO6SiNa [M
+ Na]+ 468.1818; found 468.1810.
Ethyl 2-[(2-Chlorophenyl)amino]-2-(6-hydroxybenzo[d][1,3]dioxol-5-
[1] For selected reviews, see: a) H. Amouri, J. Le Bras, Acc. Chem.
Res. 2002, 35, 501–510; b) S. B. Ferreira, F. de C. da Silva,
A. C. Pinto, D. T. G. Gonzaga, V. F. Ferreira, J. Heterocycl.
Chem. 2009, 46, 1080–1097; c) T. P. Pathak, M. S. Sigman, J.
Org. Chem. 2011, 76, 9210–9215.
[2] a) F. Doria, S. N. Richter, M. Nadai, S. Colloredo-Mels, M.
Mella, M. Palumbo, M. Freccero, J. Med. Chem. 2007, 50,
6570–6579; b) H. Wang, S. E. Rokita, Angew. Chem. 2010, 122,
6093; Angew. Chem. Int. Ed. 2010, 49, 5957–5960.
1
yl)acetate (13): H NMR (400 MHz, [D6]DMSO, 293 K): δ = 9.76
3
(s, 1 H, OH), 7.27 (d, JH,H = 7.7 Hz, 1 H, PhH), 7.11–7.07 (m, 1
3
H, PhH), 6.82 (s, 1 H, PhH), 6.72 (d, JH,H = 8.1 Hz, 1 H, PhH),
6.64–6.60 (m, 1 H, PhH), 6.46 (s, 1 H, PhH), 5.90 (s, 2 H, OCH2O),
3
3
5.66 (d, JH,H = 8.0 Hz, 1 H, NH), 5.42 (d, JH,H = 8.0 Hz, 1 H,
3
α-H), 4.17–4.02 (m, 2 H, OCH2CH3), 1.12 (t, JH,H = 7.0 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.32,
150.07, 147.30, 142.08, 139.93, 128.96, 127.97, 118.35, 117.67,
115.36, 112.13, 107.45, 100.90, 97.70, 61.06, 54.08, 13.94 ppm. IR
[3] For reviews, see: a) R. W. Van De Water, T. R. R. Pettus, Tetra-
hedron 2002, 58, 5367–5405; b) N. J. Willis, C. D. Bray, Chem.
Eur. J. 2012, 18, 9160–9173.
(KBr): ν = 3414, 3329, 3072, 2978, 2095, 1712, 1629, 1595, 1501,
˜
1444, 1371, 1327, 1285, 1262, 1210, 1171, 1136, 1104, 1035, 1020,
965, 937, 878, 862, 841, 816, 779, 751 (m), 721, 699, 609, 568, 533,
472, 440 cm–1. HRMS (ESI+): calcd. for C17H16ClNO5Na [M +
Na]+ 372.0615; found 372.0628.
[4] For examples, see: a) R. Rodriguez, R. M. Adlington, J. E. Mo-
ses, A. Cowley, J. E. Baldwin, Org. Lett. 2004, 6, 3617–3619; b)
J. E. Ezcurra, K. Karabelas, H. W. Moore, Tetrahedron 2005,
61, 275–286; c) R. Rodriguez, J. E. Moses, R. M. Adlington,
J. E. Baldwin, Org. Biomol. Chem. 2005, 3, 3488–3495; d) J.
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Kresge, Org. Biomol. Chem. 2004, 2, 1090–1092; f) K. Wojcie-
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11892–11899; h) C. Percivalle, A. La Rosa, D. Verga, F. Doria,
M. Mella, M. Palumbo, M. Di Antonio, M. Freccero, J. Org.
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14, 2929–2931; m) C. D. Bray, Org. Biomol. Chem. 2008, 6,
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T. R. R. Pettus, Org. Lett. 2011, 13, 5500–5503.
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Ethyl
2-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-morpholinoacetate
1
(14): H NMR (400 MHz, CDCl3, 293 K): δ = 6.52 (s, 1 H, PhH),
6.39 (s, 1 H, PhH), 5.87 (s, 2 H, OCH2O), 4.24–4.09 (m, 2 H,
3
OCH2CH3), 3.93 (s, 1 H, α-H), 3.76 (br. t, JH,H = 4.4 Hz, 4 H,
3
OCH2CH2N), 2.59 (br. s, 4 H, OCH2CH2N), 1.23 (t, JH,H
=
7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
169.19, 152.34, 148.66, 140.46, 109.03, 108.29, 100.99, 98.74, 73.22,
66.53, 66.53, 61.23, 50.84, 50.84, 13.89 ppm. IR (neat): ν = 3191,
˜
2966, 2855, 1736, 1632, 1559, 1504, 1480, 1454, 1408, 1388, 1369,
1329, 1300, 1269, 1237, 1187, 1141, 1117, 1072, 1034, 936, 889,
856, 768, 710, 684, 658, 524, 494 cm–1. HRMS (ESI+): calcd. for
C15H19NO6Na [M + Na]+ 332.1110; found 332.1115.
Ethyl 2-(6-Hydroxybenzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-yl)acet-
1
ate (15): H NMR (400 MHz, CDCl3, 293 K): δ = 10.31 (br. s, 1
H, OH), 6.55 (s, 1 H, PhH), 6.38 (s, 1 H, PhH), 5.86 (s, 2 H,
OCH2O), 4.21–4.09 (m, 2 H, OCH2CH3), 3.91 (s, 1 H, α-H), 2.76–
2.68 (m, 2 H, NCH2CH2), 2.63–2.55 (m, 2 H, NCH2CH2), 1.89–
3
1.81 (m, 4 H, NCH2CH2), 1.22 (t, JH,H = 7.2 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.70,
152.82, 148.22, 139.93, 110.09, 107.64, 100.76, 98.44, 72.30, 60.90,
51.74, 51.74, 23.34, 23.34, 13.81 ppm. IR (neat): ν = 3396, 2975,
˜
2886, 1732, 1626, 1542, 1504, 1479, 1456, 1244, 1181, 1036, 931,
853, 800, 769, 697 cm–1. HRMS (ESI+): calcd. for C15H20NO5 [M
+ H]+ 294.1341; found 294.1346.
Ethyl 2-(Diethylamino)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)acetate
1
(16): H NMR (400 MHz, CDCl3, 293 K): δ = 6.46 (s, 1 H, PhH),
6.41 (s, 1 H, PhH), 5.87 (s, 2 H, OCH2O), 4.50 (s, 1 H, α-H), 4.28–
4.16 (m, 2 H, OCH2CH3), 2.82–2.67 (m, 4 H, NCH2CH3), 1.27 (t,
3
3JH,H = 7.1 Hz, 3 H, OCH2CH3), 1.08 (t, JH,H = 7.2 Hz, 6 H,
[7]
[8]
S. J. Daum, P. E. Hansen, Synth. Commun. 1981, 11, 1–5.
a) E. Anakabe, J. L. Vicario, D. Badía, L. Carrillo, V. Yoldi,
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5119–5122.
NCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.01,
153.21, 148.25, 140.18, 110.02, 107.64, 100.93, 98.93, 68.12, 60.97,
43.37, 43.34, 14.12, 11.53, 11.53 ppm. IR (neat): ν = 3384, 2923,
˜
2508, 1731, 1626, 1504, 1456, 1385, 1242, 1169, 1126, 1102, 1035,
930, 880, 832, 799, 779, 760, 697, 662, 577, 472 cm–1. Because this
compound is quite unstable (see ref.[3a]), the HRMS (ESI+) molec-
ular peak was not found.
[9]
a) H. Deng, J.-K. Jung, T. Liu, K. W. Kuntz, M. L. Snapper,
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Biekert, T. Funck, Chem. Ber. 1964, 97, 363–371.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR, IR, and HRMS spectra of compounds 2,
[10]
[11]
2a–2h, 3d–3h, and 5–15 as well as additional 1H-1H COSY and
NOESY of compounds 2 for initial structure elucidation.
Eur. J. Org. Chem. 2013, 8299–8306
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8305

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Received: July 9, 2013
Published Online: November 19, 2013
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1033.
8306
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8299–8306